Highly active anti-retroviral therapy (HAART) has traditionally consisted of combination therapy with nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). These compounds inhibit biochemical processes required for viral replication. In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. While HAART has dramatically altered the prognosis for HIV infected persons, there remain many drawbacks to the current therapy including highly complex dosing regimes and side effects which can be very severe. Moreover, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance, thus limiting their utility in long term therapy. Development of new drug therapies to provide better HIV-1 treatment remains a priority.
The chemokines, a subset of the cytokine family of soluble immune modulators, are a large family of pro-inflammatory peptides that exert their pharmacological effect through G-protein-coupled receptors. The chemokines are leukocyte chemotactic proteins capable of attracting leukocytes to various tissues, which is an essential response to inflammation and infection. Human chemokines include approximately 50 structurally homologous small proteins comprising 50-120 amino acids. The CCR5 receptor is one member of this family.
Chemokine receptors have a 7 transmembrane structure and couple to a G-protein for signal transduction within a cell when bound to an agonist. Human CCR5 is composed of 352 amino acids with an intra-cellular C-terminus containing structural motifs for G-protein association and ligand-dependent signaling. The extracellular N-terminal domain contributes to high-affinity chemokine binding and interactions with the gp120 HIV protein. The natural ligands for the CCR5 are the macrophage inflammatory proteins (MIP) designated MIP-1a and MIP-1b and RANTES. The binding site for RANTES (Regulated upon Activation and is Normal T-cell Expressed and Secreted) has been shown to be on the N-terminal domain and HIV gp120 has been suggested to interact initially with the N-terminal domain and also with the ECL2 (extra-cellular loop 2).
Modulators of the CCR5 receptor may be useful in the treatment of infection by HIV-1 and genetically related retroviruses. HIV-1 infects cells of the monocyte-macrophage lineage and helper T-cell lymphocytes by exploiting a high affinity interaction of the viral enveloped glycoprotein (Env) with the CD4 antigen. The CD4 antigen appears to be a necessary, but not sufficient requirement for cell entry and at least one other surface protein is required to infect the cells. Two chemokine receptors, either the CCR5 (M-trophic strains) receptor or the CXCR4 (T-trophic strains) receptor are required, along with CD4, for infection of cells by the human immunodeficiency virus (HIV). The central role of CCR5 in the pathogenesis of HIV was inferred by epidemiological identification of powerful disease modifying effects of the naturally occurring null allele CCR5 Δ32. The Δ32 mutation has a 32-base pair deletion in the CCR5 gene resulting in a truncated protein designated Δ32. Relative to the general population, Δ32/Δ32 homozygotes are significantly common in exposed/uninfected individuals suggesting the role of CCR5 in HIV cell entry.
The HIV-1 envelope protein is comprised of two subunits: gp120, the surface subunit and gp41, the transmembrane subunit. The two subunits are non-covalently associated and form homotrimers which compose the HIV envelope. Each gp41 subunit contains two helical heptad repeat regions, HR1 and HR2 and a hydrophobic fusion region on the C-terminus.
Viral fusion and cell entry is a complex multi-step process and each step affords the potential for therapeutic intervention. The CD4 binding site on the gp120 of HIV appears to first interact with the CD4 molecule on the cell surface inducing a conformation change in gp120 which creates or exposes a cryptic CCR5 (or CXCR4) binding site, and undergoes conformational changes which permits binding of gp120 to the CCR5 and/or CXCR4 cell-surface receptor. The bivalent interaction brings the virus membrane into close proximity with the target cell membrane and the hydrophobic fusion region can insert into the target cell membrane. A conformation change in gp41 creates a contact between the outer leaflet of the target cell membrane and the viral membrane which produces a fusion pore whereby viral core containing genomic RNA enters the cytoplasm. Without being bound by theory, it is believed that the conformational changes induced by these steps expose additional targets for chemotherapeutic intervention. Each of these steps may afford an opportunity for therapeutic intervention in preventing or slowing HIV infection.
The therapeutic blockade of CCR5 as a treatment for HIV/AIDS has been demonstrated by the introduction of the CCR5 antagonist maraviroc. Clinical results suggested that maraviroc is potent and tolerable in patients with resistance to multiple antiretroviral medications. Therefore, there is a need for new and more effective CCR5 antagonists with minimal side effects and greater selectivity.
It has been unexpectedly discovered that the compounds described herein are potent modulators of CCR5 and effective antiretrovirals. Without being bound by theory, it is believed that the antiretroviral activity of these compounds results from the compounds ability to act as CCR5 antagonists.
In one illustrative embodiment of the invention, compounds of the formula
or a pharmaceutically acceptable salt thereof, wherein:
A is a conformationally constrained pyrrolidine or piperidine; or a bicyclic pyrrolidine or piperidine;
R1 is hydrogen or optionally substituted alkyl;
R2 is acyl or sulfonyl;
R3 is hydrogen or optionally substituted alkyl;
R4 is optionally substituted aryl; and
R5 is hydrogen, optionally substituted heteroaryl, acyl, acylamino, sulfonyl, or sulfonylamino are described.
In another embodiment, pharmaceutical compositions are described which comprise one or more of the compounds described herein.
In another illustrative embodiment, a method is described for treating a patient in need of relief from HIV infection, the method comprising the step of administering to the patient a therapeutically effective amount of a compound or a composition described herein.